Evidence for a Transient Additional Ligand Binding Site in the TAS2R46 Bitter Taste Receptor

J Chem Theory Comput. 2015 Sep 8;11(9):4439-49. doi: 10.1021/acs.jctc.5b00472. Epub 2015 Aug 24.


Most human G protein coupled receptors (GPCRs) are activated by small molecules binding to their 7-transmembrane (7-TM) helix bundle. They belong to basally diverging branches: the 25 bitter taste 2 receptors and most members of the very large rhodopsin-like/class A GPCRs subfamily. Some members of the class A branch have been suggested to feature not only an orthosteric agonist-binding site but also a more extracellular or "vestibular" site, involved in the binding process. Here we use a hybrid molecular mechanics/coarse-grained (MM/CG) molecular dynamics approach on a widely studied bitter taste receptor (TAS2R46) receptor in complex with its agonist strychnine. Three ∼1 μs molecular simulation trajectories find two sites hosting the agonist, which together elucidate experimental data measured previously and in this work. This mechanism shares similarities with the one suggested for the evolutionarily distant class A GPCRs. It might be instrumental for the remarkably broad but specific spectrum of agonists of these chemosensory receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Humans
  • Ligands
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / chemistry*
  • Structure-Activity Relationship
  • Strychnine / chemistry*
  • Strychnine / pharmacology


  • Ligands
  • Receptors, G-Protein-Coupled
  • taste receptors, type 2
  • Strychnine